Process for the preparation of benzoimidazol-2-yl pyrimidine derivatives

ABSTRACT

The present invention is directed to benzoimidazol-2-yl pyrimidine derivatives useful as histamine H 4  receptor modulators and processes for the preparation of such compounds.

This application claims the benefit of U.S. Provisional Application61/076,759, filed on Jun. 30, 2008, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to benzoimidazol-2-yl pyrimidinederivatives useful as histamine H₄ receptor modulators and processes forthe preparation of such compounds.

SUMMARY OF THE INVENTION

The present invention is directed to a process for the preparation ofcompounds of formula (I)

wherein

each of R¹, R², R³ and R⁴ are each independently selected from the groupconsisting of H, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, phenyl, —CF₃,—OCF₃, —CN, halo, —NO₂, —OC₁₋₄alkyl, —SC₁₋₄alkyl, —S(O)C₁₋₄alkyl,—SO₂C₁₋₄alkyl, —C(O)C₁₋₄alkyl, —C(O)phenyl, —C(O)NR^(a)R^(b),—CO₂C₁₋₄alkyl, —CO₂H, —C(O)NR^(a)R^(b), and —NR^(a)R^(b); wherein R^(a)and R^(b) are each independently selected from the group consisting ofH, C₁₋₄alkyl, and C₃₋₇cycloalkyl;

X¹ is C—R^(C); wherein R^(c) is selected from the group consisting of H,methyl, hydroxymethyl, dimethylaminomethyl, ethyl, propyl, isopropyl,—CF₃, cyclopropyl, and cyclobutyl; and X² is N;

n is 1 or 2;

Z is selected from the group consisting of N, CH, and C(C₁₋₄alkyl);

R⁶ is selected from the group consisting of H, C₁₋₆alkyl, and amonocyclic cycloalkyl;

R⁸ is selected from the group consisting of H and C₁₋₄alkyl;

R⁹, R¹⁰ and R¹¹ are each independently selected from the groupconsisting of H and C₁₋₄alkyl;

and pharmaceutically acceptable salts, pharmaceutically acceptableprodrugs, and pharmaceutically active metabolites thereof; comprising

reacting a compound of formula (V) with a reducing agent system; in asolvent; at a temperature in the range of from about 0° C. to about 25°C.; to yield compound of formula (VI); and

reacting compound of formula (VI) with a compound of formula (VII); inthe presence of a suitably selected oxidizing agent or oxidizing agentsystem, in water or in an organic solvent, at a temperature in the rangeof from about 25° C. to about 100° C.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I-A)

(also known as[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine)or a pharmaceutically acceptable salt, or a pharmaceutically acceptableprodrug, or a pharmaceutically active metabolite thereof; comprising

reacting a compound of formula (V-S) with a reducing agent system; in asolvent; at a temperature in the range of from about 0° C. to about 25°C., to yield compound of formula (VI-S); and

reacting compound of formula (VI-S) with a compound of formula (VII-A);in the presence of a suitably selected oxidizing agent or oxidizingagent system, in water or in an organic solvent, at a temperature in therange of from about 25° C. to about 100° C., to yield compound offormula (I-A).

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I-B)

(also known as[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine)or a pharmaceutically acceptable salt, or a pharmaceutically acceptableprodrug, or a pharmaceutically active metabolite thereof; comprising

reacting a compound of formula (V-S) with a reducing agent system; in asolvent; at a temperature in the range of from about 0° C. to about 25°C., to yield compound of formula (VI-S); and

reacting compound of formula (VI-S) with a compound of formula (VII-B);in the presence of a suitably selected oxidizing agent or oxidizingagent system, in water or in an organic solvent, at a temperature in therange of from about 25° C. to about 100° C., to yield compound offormula (I-B).

The present invention is directed to a product prepared according to anyof the processes described herein. The present invention is furtherdirected to a crystalline hemi-tartrate of compound of formula (I-A).The present invention is further directed to a process for thepreparation of a hemi-tartrate of compound of formula (I-A). The presentinvention is further directed to a process for the recrystallization ofthe hemi-tartrate of compound of formula (I-A).

In a further general aspect, the invention relates to pharmaceuticalcompositions each comprising: (a) an effective amount of at least oneagent selected from compounds of Formula (I), prepared according to theprocess as described herein; and pharmaceutically acceptable salts,pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites thereof; and (b) a pharmaceutically acceptable excipient.

In another general aspect, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or medical condition mediated by histamine H₄ receptor activity,comprising administering to the subject in need of such treatment aneffective amount of at least one compound of Formula (I), or apharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically active metabolite of such compound, wherein compoundof formula (I), pharmaceutically acceptable salt, prodrug or metabolitethereof is prepared according to the process as described herein. Incertain embodiments of the inventive method, the disease, disorder, ormedical condition is inflammation. Inflammation herein refers to theresponse that develops as a consequence of histamine release, which inturn is caused by at least one stimulus. Examples of such stimuli areimmunological stimuli and non-immunological stimuli.

In another general aspect, the invention is directed to a method formodulating histamine H₄ receptor activity, comprising exposing histamineH₄ receptor to an effective amount of at least one of a compound ofFormula (I) and a pharmaceutically acceptable salt, prodrug ormetabolite thereof; wherein compound of formula (I), pharmaceuticallyacceptable salt, prodrug or metabolite thereof is prepared according tothe process as described herein.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a powder X-ray diffraction (XRD) pattern for acrystalline hemi-tartrate of compound of formula (I-A).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a process for the preparation ofcompound of formula (I)

wherein R¹, R², R³, R⁴, X¹, X², R⁶, R⁸, Z, n, R⁹, R¹⁰ and R¹¹ are asherein defined. Embodiments of compounds of the present invention areuseful as histamine H₄ receptor modulators.

In an embodiment of the present invention, compound of formula (I) isselected from the group consisting of a compound of formula (I-A)

and pharmaceutically acceptable salts thereof; and a compound of formula(I-B)

and pharmaceutically acceptable salts thereof.

In some embodiments of compounds of Formula (I), each of R¹⁻⁴ isindependently H, methyl, tert-butyl, methoxy, —CF₃, —CN, fluoro, chloro,methoxycarbonyl, or benzoyl. In some embodiments, X² is N. In otherembodiments, X¹ is N. In some embodiments, R^(c) is H, methyl, ethyl,CF₃, cyclopropyl, or cyclobutyl. In further embodiments, R^(c) is H ormethyl. In some embodiments, n is 1. In some embodiments, Z is N or CH.In further embodiments, Z is CH. In some embodiments, R⁶ is H, methyl,ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. In furtherembodiments, R⁶ is H or methyl. In some embodiments, R⁸ is H. In someembodiments, R⁹ and R¹⁰ are each independently H or methyl. In furtherembodiments, R⁹ and R¹⁰ are both H. In some embodiments, R¹¹ is H ormethyl. In further embodiments, R¹¹ is methyl.

In an embodiment, the present invention is directed to a process for thepreparation of compounds of formula (I)

wherein R¹, R², R³, R⁴, X¹, X², R⁶, R⁸, R⁹, R¹⁰, R¹¹ and n are as hereindefined; and pharmaceutically acceptable salts, pharmaceuticallyacceptable prodrugs, and pharmaceutically active metabolites thereof;comprising

reacting a compound of formula (VI) with a compound of formula (VII); inthe presence of a suitably selected oxidizing agent or oxidizing agentsystem, in water or in an organic solvent, at a temperature in the rangeof from about 25° C. to about 100° C.; to yield the compound of formula(I).

In another embodiment, the present invention is directed to a processfor the preparation of a compound of formula (I-A)

(also known as[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine)or a pharmaceutically acceptable salt, or a pharmaceutically acceptableprodrug, or a pharmaceutically active metabolite thereof; comprising

reacting a compound of formula (VI-S) with a compound of formula(VII-A); in the presence of a suitably selected oxidizing agent oroxidizing agent system, in water or in an organic solvent, at atemperature in the range of from about 25° C. to about 100° C., to yieldcompound of formula (I-A).

In yet another embodiment, the present invention is directed to aprocess for the preparation of a compound of formula (I-B)

(also known as[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine)or a pharmaceutically acceptable salt, or a pharmaceutically acceptableprodrug, or a pharmaceutically active metabolite thereof; comprising

reacting a compound of formula (VI-S) with a compound of formula(VII-B); in the presence of a suitably selected oxidizing agent oroxidizing agent system, in water or in an organic solvent, at atemperature in the range of from about 25° C. to about 100° C., to yieldcompound of formula (I-B).

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The terms “halogen” and “halo” represents chlorine, fluorine, bromine,or iodine. The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by thesymbol “/”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples.

The term “alkenyl” refers to a straight- or branched-chain alkenyl grouphaving from 2 to 12 carbon atoms in the chain. (The double bond of thealkenyl group is formed by two sp² hybridized carbon atoms.)Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl,2-methylprop-2-enyl, hex-2-enyl, and groups that in light of theordinary skill in the art and the teachings provided herein would beconsidered equivalent to any one of the foregoing examples.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

When a particular group is “substituted” (e.g., alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, etc.), that group may have one or moresubstituents, for example, from one to five substituents, or from one tothree substituents, or one to two substituents, independently selectedfrom the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof.

Furthermore, certain structures may exist as geometric isomers (i.e.,cis and trans isomers), as tautomers, or as atropisomers. Additionally,any formula given herein is intended to represent hydrates, solvates,and polymorphs of such compounds, and mixtures thereof.

Reference to a chemical entity herein stands for a reference to any oneof: (a) the actually recited form of such chemical entity, and (b) anyof the forms of such chemical entity in the medium in which the compoundis being considered when named. For example, reference herein to acompound such as R—COOH, encompasses reference to any one of, forexample, R—COOH(s), R—COOH_((sol)), and R—COO⁻ _((sol)). In thisexample, R—COOH(s) refers to the solid compound, as it could be forexample in a tablet or some other solid pharmaceutical composition orpreparation; R—COOH_((sol)) refers to the undissociated form of thecompound in a solvent; and R—COO⁻ _((sol)) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO⁻ upon dissociation in the medium being considered. Inanother example, an expression such as “exposing an entity to compoundof formula R—COOH”refers to the exposure of such entity to the form, orforms, of the compound R—COOH that exists, or exist, in the medium inwhich such exposure takes place. In this regard, if such entity is forexample in an aqueous environment, it is understood that the compoundR—COOH is in such same medium, and therefore the entity is being exposedto species such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where thesubscript “(aq)” stands for “aqueous” according to its conventionalmeaning in chemistry and biochemistry. A carboxylic acid functionalgroup has been chosen in these nomenclature examples; this choice is notintended, however, as a limitation but it is merely an illustration. Itis understood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation. In another example, a zwitterionic compound isencompassed herein by referring to a compound that is known to form azwitterions, even if it is not explicitly named in its zwitterionicform. Terms such as zwitterion, zwitterions, and their synonymszwitterionic compound(s) are standard IUPAC-endorsed names that are wellknown and part of standard sets of defined scientific names. In thisregard, the name zwitterion is assigned the name identificationCHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI)dictionary of molecular entities. (See, for example its on line versionat http://www.ebi.ac.uk/chebi/init.do). As generally well known, azwitterion or zwitterionic compound is a neutral compound that hasformal unit charges of opposite sign. Sometimes these compounds arereferred to by the term “inner salts”. Other sources refer to thesecompounds as “dipolar ions”, although the latter term is regarded bystill other sources as a misnomer. As a specific example, aminoethanoicacid (the amino acid glycine) has the formula H₂NCH₂COOH, and it existsin some media (in this case in neutral media) in the form of thezwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds, inner saltsand dipolar ions in the known and well established meanings of theseterms are within the scope of this invention, as would in any case be soappreciated by those of ordinary skill in the art. Because there is noneed to name each and every embodiment that would be recognized by thoseof ordinary skill in the art, no structures of the zwitterioniccompounds that are associated with the compounds of this invention aregiven explicitly herein. They are, however, part of the embodiments ofthis invention when compounds referred to herein can form zwitterions.No further examples in this regard are provided herein because theseinteractions and transformations in a given medium are known by any oneof ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹F,³⁸Cl, ¹²⁵I, respectively. Such isotopically labelled compounds areuseful in metabolic studies (for example with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly preferredfor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S¹ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₄; and equivalents of each one of such choices. Theshorter terminology “S¹ _(example) is one of S₁ and S₂, and S²_(example) is one of S₃ and S₄” is accordingly used herein for the sakeof brevity, but not by way of limitation. The foregoing first example onsubstituent terminology, which is stated in generic terms, is meant toillustrate the various substituent assignments described herein. Theforegoing convention given herein for substituents extends, whenapplicable, to members such as R¹⁻¹¹, X¹, X², and n, and any othergeneric substituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such asR¹⁻¹¹, X¹, X², and n, and any other generic substituent symbol usedherein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B—, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows

DDQ=2,3-Dichloro-5,6-dicyanobenzoquinone

Dibal-H, DIBAL-H=Diisobutylaluminum hydride

DMA=Dimethylacetamide

DME=1,2-Dimethoxyethane

DMF=N,N-Dimethylformamide

EtOH=Ethanol

HPLC=High Pressure Liquid Chromatography

IPA=Isopropyl alcohol

2-Me-THF=2-Methyl-tetrahydrofuran

MTBE=Methyl-t-butyl ether

NMM=N-Methylmorpholine

NMP=1-Methyl-2-pyrrolidinone

OXONE®=Potassium monopersulphate triple salt

RANEY® Nickel=Aluminum-nickel alloy

Red-AI=Sodium bis(2-methoxyethoxy)aluminum hydride

TEA=Triethylamine

TEMPO®=[2,2,6,6-tetramethyl-1-piperidinyloxy free radical]

THF=Tetrahydrofuran

XRD=X-Ray Diffraction

As used herein, unless otherwise noted, the term “isolated form” shallmean that the compound is present in a form which is separate from anysolid mixture with another compound(s), solvent system or biologicalenvironment. In an embodiment of the present invention, compound offormula (I) is prepared as an isolated form. In another embodiment ofthe present invention, compound of formula (I-A) is prepared as anisolated form. In another embodiment of the present invention, compoundof formula (I-B) is prepared as an isolated form.

As used herein, unless otherwise noted, the term “substantially pure”shall mean that the mole percent of impurities in the isolated compoundis less than about 5 mole percent, for example, at less than about 2mole percent. In an embodiment, the mole percent of impurities is lessthan about 0.5 mole percent, for example, less than about 0.1 molepercent. In an embodiment of the present invention, compound of formula(I) is prepared as a substantially pure compound. In another embodimentof the present invention, compound of formula (I-A) is prepared asubstantially pure compound. In another embodiment of the presentinvention, compound of formula (I-B) is prepared a substantially purecompound.

As used herein, unless otherwise noted, the term “substantially free ofa corresponding salt(s)” when used to described compound of formula (I)shall mean that mole percent of the corresponding salt form(s) in theisolated base of formula (I) is less than about 5 mole percent, forexample, less than about 2 mole percent. In an embodiment, the molepercent of the corresponding salt form(s) is less than about 0.5 molepercent, for example, less than about 0.1 mole percent. In an embodimentof the present invention, compound of formula (I) is prepared in a formwhich is substantially free of corresponding salt. In another embodimentof the present invention, compound of formula (I-A) is prepared in aform which is substantially free of corresponding salt. In anotherembodiment of the present invention, compound of formula (I-B) isprepared in a form which is substantially free of corresponding salt.

The invention includes also pharmaceutically acceptable salts of thecompounds represented by Formula (I), for example those described aboveand of the specific compounds exemplified herein.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceuticallyacceptable salts are those that are pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. A compound of Formula (I)may possess a sufficiently acidic group, a sufficiently basic group, orboth types of functional groups, and accordingly react with a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. Examples of pharmaceuticallyacceptable salts include sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

If compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, ethanesulfonic acid, any compatible mixture ofacids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

If compound of Formula (I) is an acid, such as a carboxylic acid orsulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as glycine and arginine, ammonia,carbonates, bicarbonates, primary, secondary, and tertiary amines, andcyclic amines, such as pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The invention also relates to treatment methods employingpharmaceutically acceptable prodrugs of compounds of Formula (I). Theterm “prodrug” means a precursor of a designated compound that,following administration to a subject, yields the compound in vivo via achemical or physiological process such as solvolysis or enzymaticcleavage, or under physiological conditions (e.g., a prodrug on beingbrought to physiological pH is converted to compound of Formula (I)). A“pharmaceutically acceptable prodrug” is a prodrug that is not toxic,biologically intolerable, or otherwise biologically unsuitable foradministration to the subject. Illustrative procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Examples of prodrugs include compounds having an amino acid residue, ora polypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Adv. Drug Delivery Rev. 1996, 19,115. Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in J. Med.Chem. 1996, 39, 10. Free amines can also be derivatized as amides,sulfonamides or phosphonamides. All of these prodrug moieties mayincorporate groups including ether, amine, and carboxylic acidfunctionalities.

Pharmaceutically active metabolites may also be used in the methods ofthe invention. A “pharmaceutically active metabolite” means apharmacologically active product of metabolism in the body of a compoundof Formula (I) or salt thereof. Prodrugs and active metabolites of acompound may be determined using routine techniques known or availablein the art. See, e.g., Bertolini, et al., J. Med. Chem. 1997, 40,2011-2016; Shan, et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe,Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13,224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites (collectively, “agents”) of the present invention are usefulas histamine H₄ receptor modulators in the methods of the invention. Theagents may be used in the inventive methods for the treatment orprevention of medical conditions, diseases, or disorders mediatedthrough modulation of the histamine H₄ receptor, such as those describedherein. Agents according to the invention may therefore be used as ananti-inflammatory agents. Symptoms or disease states are intended to beincluded within the scope of “medical conditions, disorders, ordiseases.”

Accordingly, the invention relates to methods of using thepharmaceutical agents described herein to treat subjects diagnosed withor suffering from a disease, disorder, or condition mediated throughhistamine H₄ receptor activity, such as inflammation.

In another embodiment, an agent of the present invention is administeredto treat inflammation. Inflammation may be associated with variousdiseases, disorders, or conditions, such as inflammatory disorders,allergic disorders, dermatological disorders, autoimmune disease,lymphatic disorders, and immunodeficiency disorders, including the morespecific conditions and diseases given below. Regarding the onset andevolution of inflammation, inflammatory diseases orinflammation-mediated diseases or conditions include, but are notlimited to, acute inflammation, allergic inflammation, and chronicinflammation.

Illustrative types of inflammation treatable with a histamine H₄receptor-modulating agent according to the invention includeinflammation due to or associated with any one of a plurality ofconditions such as allergy, asthma, dry eye, chronic obstructedpulmonary disease (COPD), atherosclerosis, rheumatoid arthritis,multiple sclerosis, inflammatory bowel diseases (including colitis,Crohn's disease, and ulcerative colitis), psoriasis, pruritis, itchyskin, atopic dermatitis, urticaria (hives), ocular inflammation,conjunctivitis, nasal polyps, allergic rhinitis, nasal itch,scleroderma, autoimmune thyroid diseases, immune-mediated (also known astype 1) diabetes mellitus and lupus, which are characterized byexcessive or prolonged inflammation at some stage of the disease. Otherautoimmune diseases that lead to inflammation include Myasthenia gravis,autoimmune neuropathies, such as Guillain-Barré, autoimmune uveitis,autoimmune hemolytic anemia, pernicious anemia, autoimmunethrombocytopenia, temporal arteritis, anti-phospholipid syndrome,vasculitides, such as Wegener's granulomatosis, Behcet's disease,dermatitis herpetiformis, pemphigus vulgaris, vitiligio, primary biliarycirrhosis, autoimmune hepatitis, autoimmune oophoritis and orchitis,autoimmune disease of the adrenal gland, polymyositis, dermatomyositis,spondyloarthropathies, such as ankylosing spondylitis, and Sjogren'ssyndrome.

Pruritis with a histamine H₄ receptor-modulating agent according to theinvention includes that which is a symptom of allergic cutaneousdiseases (such as atopic dermatitis and hives) and other metabolicdisorders (such as chronic renal failure, hepatic cholestasis, anddiabetes mellitus).

In another embodiment, an agent of the present invention is administeredto treat allergy, asthma, autoimmune diseases, or pruritis.

The term “treat” or “treating” as used herein is intended to refer toadministration of an agent or composition of the invention to a subjectfor the purpose of effecting a therapeutic or prophylactic benefitthrough modulation of histamine H₄ receptor activity. Treating includesreversing, ameliorating, alleviating, inhibiting the progress of,lessening the severity of, or preventing a disease, disorder, orcondition, or one or more symptoms of such disease, disorder orcondition mediated through modulation of histamine H₄ receptor activity.The term “subject” refers to a mammalian patient in need of suchtreatment, such as a human. “Modulators” include both inhibitors andactivators, where “inhibitors” refer to compounds that decrease,prevent, inactivate, desensitize or down-regulate histamine H₄ receptorexpression or activity, and “activators” are compounds that increase,activate, facilitate, sensitize, or up-regulate histamine H₄ receptorexpression or activity.

In treatment methods according to the invention, an effective amount ofat least one pharmaceutical agent according to the invention isadministered to a subject suffering from or diagnosed as having such adisease, disorder, or condition. An “effective amount” means an amountor dose sufficient to generally bring about the desired therapeutic orprophylactic benefit in patients in need of such treatment for thedesignated disease, disorder, or condition. Effective amounts or dosesof the agents of the present invention may be ascertained by routinemethods such as modeling, dose escalation studies or clinical trials,and by taking into consideration routine factors, e.g., the mode orroute of administration or drug delivery, the pharmacokinetics of theagent, the severity and course of the disease, disorder, or condition,the subject's previous or ongoing therapy, the subject's health statusand response to drugs, and the judgment of the treating physician. Anexample of a dose is in the range of from about 0.01 to about 200 mg ofagent per kg of subject's body weight per day, or any range therein; forexample about 0.05 to 100 mg/kg/day, or any range therein; or forexample, about 1 to 35 mg/kg/day, or any range therein; in single ordivided dosage units (e.g., BID, TID, QID). For a 70-kg human, anillustrative range for a suitable dosage amount is from about 0.05 toabout 7 g/day, or any range therein; for example about 0.1 to about 2.5g/day, or any range therein; for example 0.2 to about 1.0 g/day, or anyrange therein.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the agents of the invention may be used in combination withadditional active compounds in the treatment of the above conditions.The additional compounds may be coadministered separately with an agentof Formula (I) or included with such an agent as an additional activeingredient in a pharmaceutical composition according to the invention.In an illustrative embodiment, additional active compounds are thosethat are known or discovered to be effective in the treatment ofconditions, disorders, or diseases mediated by histamine H₄ receptoractivity, such as another histamine H₄ receptor modulator or a compoundactive against another target associated with the particular condition,disorder, or disease. The combination may serve to increase efficacy(e.g., by including in the combination a compound potentiating thepotency or effectiveness of an agent according to the invention),decrease one or more side effects, or decrease the required dose of theagent according to the invention.

When referring to modulating the target receptor, an “effective amount”means an amount sufficient to affect the activity of such receptor.Measuring the activity of the target receptor may be performed byroutine analytical methods. Target receptor modulation is useful in avariety of settings, including assays.

The agents of the invention are used, alone or in combination with oneor more other active ingredients, to formulate pharmaceuticalcompositions of the invention. A pharmaceutical composition of theinvention comprises an effective amount of at least one pharmaceuticalagent in accordance with the invention. A pharmaceutically acceptableexcipient is part of some embodiments of pharmaceutical compositionsaccording to this invention.

A “pharmaceutically acceptable excipient” refers to a substance that isnot toxic, biologically intolerable, or otherwise biologicallyunsuitable for administration to a subject, such as an inert substance,added to a pharmacological composition or otherwise used as a vehicle,carrier, or diluent to facilitate administration of a pharmaceuticalagent and that is compatible therewith. Examples of excipients includecalcium carbonate, calcium phosphate, various sugars and types ofstarch, cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the pharmaceutical agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those of ordinary skill in the art. The compositionsmay be administered in the inventive methods by a suitable route ofdelivery, e.g., oral, parenteral, rectal, topical, or ocular routes, orby inhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. In an example, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the agents may beformulated to yield a dosage of, e.g., from about 0.01 to about 200mg/kg daily, or any range therein; for example from about 0.05 to about100 mg/kg daily, or any range therein; or for example from about 0.05 toabout 50 mg/kg daily, or any range therein; or for example from about0.05 to about 25 mg/kg/day, or any range therein; or for example, fromabout 0.1 to about 10 mg/kg/day, or any range therein.

Oral tablets may include the agent and any other active ingredientsmixed with compatible pharmaceutically acceptable excipients such asdiluents, disintegrating agents, binding agents, lubricating agents,sweetening agents, flavoring agents, coloring agents and preservativeagents. Suitable inert fillers include sodium and calcium carbonate,sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like.Examples of liquid oral excipients include ethanol, glycerol, water, andthe like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate,microcrystalline cellulose, and alginic acid are examples ofdisintegrating agents. Binding agents may include starch and gelatin.The lubricating agent, if present, may be magnesium stearate, stearicacid or talc. If desired, the tablets may be coated with a material suchas glyceryl monostearate or glyceryl distearate to delay absorption inthe gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient may be mixed with asolid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, theagents of the invention may be provided in sterile aqueous solutions orsuspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms may be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses rangefrom about 1 to 1000 μg/kg/minute of agent, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the agents may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the agents of theinvention may utilize a patch formulation to affect transdermaldelivery.

Agents may alternatively be administered in methods of this invention byinhalation, via the nasal or oral routes, e.g., in a spray formulationalso containing a suitable carrier.

Examples of agents useful in methods of the invention will now bedescribed by reference to illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I).

As more extensively provided in this written description, terms such as“reacting” and “reacted” are used herein in reference to a chemicalentity that is any one of: (a) the actually recited form of suchchemical entity, and (b) any of the forms of such chemical entity in themedium in which the compound is being considered when named.

One of ordinary skill in the art will recognize that, where nototherwise specified, the reaction step(s) is performed under suitableconditions, according to known methods, to provide the desired product.One of ordinary skill in the art will further recognize that, in thespecification and claims as presented herein, wherein a reagent orreagent class/type (e.g., base, solvent, etc.) is recited in more thanone step of a process, the individual reagents are independentlyselected for each reaction step and may be the same of different fromeach other. For example wherein two steps of a process recite an organicor inorganic base as a reagent, the organic or inorganic base selectedfor the first step may be the same or different than the organic orinorganic base of the second step. Further, one of ordinary skill in theart will recognize that wherein a reaction step of the present inventionmay be carried out in a variety of solvents or solvent systems, saidreaction step may also be carried out in a mixture of the suitablesolvents or solvent systems.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any rangetherein.

Examples of suitable solvents, bases, reaction temperatures, and otherreaction parameters and components are provided in the detaileddescriptions which follows herein. One of ordinary skill in the art willrecognize that the listing of said examples is not intended, and shouldnot be construed, as limiting in any way the invention set forth in theclaims which follow thereafter.

As used herein, unless otherwise noted, the term “aprotic solvent” shallmean any solvent that does not yield a proton. Suitable examplesinclude, but are not limited to DMF, 1,4-dioxane, THF, acetonitrile,pyridine, dichloroethane, dichloromethane, MTBE, toluene and acetone.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, cyano and triflate.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Illustrative suitablenitrogen protecting groups include, but are not limited to, carbamates(which are groups that contain a moiety —C(O)O—R, wherein R is forexample methyl, ethyl, t-butyl, benzyl, phenylethyl, CH₂═CH—CH₂— and2,2,2-trichloroethyl); amides (which are groups that contain a moiety—C(O)—R′, wherein R′ is for example methyl, phenyl, trifluoromethyl andt-butyl (pivalol)); N-sulfonyl derivatives (which are groups thatcontain a moiety —SO₂—R″, wherein R″ is for example methyl, tolyl,phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl- and2,3,6-trimethyl-4-methoxybenzene). Other suitable nitrogen protectinggroups may be found in texts such as P. G. M. Wuts & T. W. GreeneProtective Groups in Organic Synthesis, John Wiley & Sons, 2007, andProtective Groups in Organic Chemistry, ed. J. F. W. McOmie, PlenumPress, 1973.

One of ordinary skill in the art will recognize that wherein a reactionstep of the present invention may be carried out in a variety ofsolvents or solvent systems, said reaction step may also be carried outin a mixture of the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and P. G. M. Wuts & T. W. Greene ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 2007. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention is directed to a process for the preparation of acompound of formula (I) as outlined in more detail in Scheme 1, below.

Referring to Scheme 1, a suitably substituted compound of formula (V), aknown compound or compound prepared by known methods, is reacted with asuitably selected reducing agent system such as DIBAL-H, RANEY® nickelin the presence of a source of hydrogen such as H₂(g), formic acid, andany other source of hydrogen that behaves like H₂(g) and formic acidunder these conditions, Red-AI, sodium borohydride, cupric hydride orlithium triethylborohydride, to yield compound of formula (VI). In someembodiments DIBAL-H or RANEY® nickel is used in the presence of a sourceof hydrogen. When the reducing agent system is a single agent, such asDIBAL-H, the reducing agent system is present in an amount in the rangeof from about 1.0 to about 5.0 molar equivalents (relative to the molesof compound of formula (V). In some embodiments, in an amount in therange of from about 2.0 to about 3.0 molar equivalents. In otherembodiments, at about 2.5 molar equivalent. In an another example, thereducing agent system is RANEY® nickel in the presence of a source ofhydrogen and RANEY® nickel is present in an amount in the range of fromabout 1.0 to about 10.0 molar equivalents, for example at about 200% byweight. In another example, the source of hydrogen is formic acid, andthe formic acid is present in excess amount, for example at about 40molar equivalents.

Examples of suitable solvents include the following. Where the reducingagent system is DIBAL-H, the reduction can be performed in an organicsolvent, such as THF, toluene, 2-Me-THF, DME or MTBE. Such organicsolvent may be an anhydrous organic solvent, such as THF ortoluene. Inanother example, the reducing agent system is RANEY® nickel and a sourceof hydrogen such as formic acid, in water. The reaction temperature isin the range of from about 0° C. to about 25° C. In some embodiments,where the reducing agent system is DIBAL-H, the temperature is fromabout 5° C. to about 10° C. In other embodiments, where the reducingagent system is RANEY® nickel and a source of hydrogen such as formicacid, the temperature is about room temperature.

Compound of formula (VI) is reacted with a suitably substituted compoundof formula (VII) to yield compound of formula (I), such compound offormula (VII) being present as a free base or as its corresponding saltform, a known compound or compound prepared by known methods. Compoundof formula (VII) is present in an amount in the range of from about 1.0to about 1.25 molar equivalents, for example in an amount in the rangeof from about 1.0 to about 1.1 molar equivalents, for example at about1.01 molar equivalents. This reaction is performed in the presence of asuitably selected oxidizing agent or oxidizing agent system, such asNa₂SO₃/air, Na₂S₂O₅/air, NaHSO₃/air, DDQ, OXONE® or TEMPO® incombination with sodium hypochlorite, for example Na₂SO₃/air orNa₂S₂O₅/air. The term “oxidizing agent system” is herein used togenerically refer to any such oxidizing agent or oxidizing agent system.Such oxidizing agent or oxidizing agent system is present in an amountin the range of from about 0.90 to about 1.5 molar equivalents, forexample in an amount in the range of from about 0.95 to about 1.3 molarequivalents, for example in an amount of about 1.3 molar equivalents,and still in another example in an amount of about 1.0 molarequivalents. This reaction's medium is water in some embodiments or anorganic solvent in other embodiments. Examples of such organic solventsinclude DMF, NMP, DMA, acetonitrile and ethanol. Some reaction media areDMF, and in other examples, they are water. This reaction is performedat a temperature in the range of from about 25° C. to about 100° C., forexample at a temperature in the range of from about 55° C. to about 65°C.

One of ordinary skill in the art will recognize that when compound offormula (VI) is reacted with compound of formula (VII) as itscorresponding salt form in an organic solvent, then the reaction is runin the presence of a suitably selected organic or inorganic base such assuch as NMM, TEA or K₂CO₃, for example K₂CO₃. One of ordinary skill inthe art will further recognize that the base is present to neutralizethe salt form of compound of formula (VII) and thereby liberate thediamine compound of formula (VII). One of ordinary skill in the art willfurther recognize that compound of formula (VI) may alternatively bereacted with compound of formula (VII) as its corresponding salt form inwater, in the presence of a suitably selected acid such as HCl, H₂SO₄,and any other acid that behaves like any of these acids in the presentreaction conditions.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I-A), as outlined in more detailin Scheme 2, below.

Referring to Scheme 2, a suitably substituted compound of formula (V-S),a known compound or compound prepared by known methods, is reacted witha suitably selected reducing agent system to yield to yield compound offormula (VI-S). Examples of reducing agent systems include DIBAL-H,RANEY® nickel in the presence of a source of hydrogen such as H₂(g),formic acid, and any other hydrogen source that behaves under theseconditions like hydrogen gas and formic acid, Red-AI, sodiumborohydride, cupric hydride or lithium triethylborohydride. In someembodiments, the reducing agent system is DIBAL-H or RANEY® nickel inthe presence of a source of hydrogen.

Where the reducing agent system is a single agent such as DIBAL-H, thereducing agent system is present in an amount in the range of from about1.0 to about 5.0 molar equivalents (relative to the moles of compound offormula (V-S). In other embodiments, in an amount in the range of fromabout 2.0 to about 3.0 molar equivalents. Still in other embodiments atabout 2.5 molar equivalent.

In other embodiments, the reducing agent system is RANEY® nickel in thepresence of a source of hydrogen and RANEY® nickel is present in anamount in the range of from about 1.0 to about 10.0 molar equivalents,for example at about 200% by weight. In other embodiments, the source ofhydrogen is formic acid, and the formic acid is present in excessamount, for example at about 40 molar equivalents.

Examples of solvents for this reaction include the following. Thereducing agent system DIBAL-His used in an organic solvent, such as THF,toluene, 2-Me-THF, DME and MTBE. In some embodiments, the organicsolvent is an anhydrous organic solvent, for example in THF or toluene.The reducing agent system RANEY® nickel and a source of hydrogen, suchas formic acid, the solvent is water. The temperature is in the range offrom about 0° C. to about 25° C. When the reducing agent system isDIBAL-H, then the temperature is from about 5 to about 10° C. In anotherexample, where the reducing agent system is RANEY® nickel and a sourceof hydrogen, such as formic acid, the reaction is performed at aboutroom temperature.

Compound of formula (VI-S) is reacted with a suitably substitutedcompound of formula (VII-A), to yield compound of formula (I-A), whereincompound of formula (VII-A) may be present as a free base or as itscorresponding salt form, a known compound or compound prepared by knownmethods. Compound of formula (VII-A) is present in an amount in therange of from about 1.0 to about 1.25 molar equivalents. In someembodiments, it is present in an amount in the range of from about 1.0to about 1.1 molar equivalents. In still other embodiments, at about1.01 molar equivalents. This reaction is performed in the presence of asuitably selected oxidizing agent or oxidizing agent system, such asNa₂SO₃/air, Na₂S₂O₅/air, NaHSO₃/airDDQ, OXONE® or TEMPO® in combinationwith sodium hypochlorite. In some embodiments, this oxidizing agentsystem is Na₂SO₃/air or Na₂S₂O₅/air. The oxidizing agent or oxidizingagent system is present in an amount in the range of from about 0.90 toabout 1.5 molar equivalents. In some embodiments, in an amount in therange of from about 0.95 to about 1.3 molar equivalents. In otherembodiments, in an amount of about 1.3 molar equivalents, and still inother embodiments in an amount of about 1.0 molar equivalents. Themedium for this reaction is water or an organic solvent such as DMF,NMP, DMA, acetonitrile and ethanol. In some embodiments, the medium isDMF, and in other examples, it is water. The reaction temperature is inthe range of from about 25° C. to about 100° C. In some embodiments, thetemperature is in the range of from about 55° C. to about 65° C.

One of ordinary skill in the art will recognize that when compound offormula (VI-S) is reacted with compound of formula (VII-A) as itscorresponding salt form in an organic solvent, then the reaction is runin the presence of a suitably selected organic or inorganic base such assuch as NMM, TEA or K₂CO₃, for example K₂CO₃. One of ordinary skill inthe art will further recognize that the base is present to neutralizethe salt form of compound of formula (VII-A) and thereby liberate thediamine compound of formula (VII-A). One of ordinary skill in the artwill further recognize that compound of formula (VI-A) may alternativelybe reacted with compound of formula (VII-A) as its corresponding saltform in water, in the presence of a suitably selected acid such as HCl,H₂SO₄, and any other acid that behaves like hydrochloric and sulfuricacids in these conditions.

In an embodiment, the present invention is directed to a process for thepreparation of a compound of formula (I-B), as outlined in more detailin Scheme 3, below.

With reference to Scheme 3, a suitably substituted compound of formula(V-S), a known compound or compound prepared by known methods, isreacted with a suitably selected reducing agent system such as Dibal-H,RANEY® nickel in the presence of a source of hydrogen such as H₂(g),formic acid, and any other hydrogen source that behaves under theseconditions as hydrogen gas and formic acid do, Red-AI, sodiumborohydride, cupric hydride or lithium triethylborohydride, to yield thecompound of formula (VI-S). In some embodiments, the reducing agentsystem is Dibal-H or RANEY® nickel in the presence of a source ofhydrogen.

In an embodiment, where the reducing agent system is a single agent,such as DIBAL-H, the reducing agent system is present in an amount inthe range of from about 1.0 to about 5.0 molar equivalents (relative tothe moles of compound of formula (V-S). In another embodiment, in anamount in the range of from about 2.0 to about 3.0 molar equivalents,and still in other embodiments, in an amount of about 2.5 molarequivalent.

Where the reducing agent system is RANEY® nickel in the presence of asource of hydrogen, RANEY® nickel is present in an amount in the rangeof from about 1.0 to about 10.0 molar equivalents, for example at about200% by weight. Where the source of hydrogen is formic acid, it ispresent in an excess amount, for example about 40 molar equivalents offormic acid.

Examples of solvents for this reaction are the following where thereducing agent system is DIBAL-H, the solvent is an organic solvent,such as THF, toluene, 2-Me-THF, DME and MTBE. Such organic solvent mayin some embodiments be an anhydrous organic solvent, for example THF ortoluene. Where the reducing agent system is RANEY® nickel and the sourceof hydrogen is formic acid, the solvent is typically water.

The reaction temperature is in the range of from about 0° C. to about25° C. In some embodiments, where the reducing agent system is DIBAL-H,the temperature is from about 5° C. to about 10° C. In otherembodiments, where the reducing agent system is RANEY® nickel with asource of hydrogen such as formic acid, the temperature is about roomtemperature.

Compound of formula (VI-S) is reacted with a suitably substitutedcompound of formula (VII-B), wherein compound of formula (VII-B) may bepresent as a free base or as its corresponding salt form, a knowncompound or compound prepared by known methods, to yield the compound offormula (I-B). Compound of formula (VII-B) is present in an amount inthe range of from about 1.0 to about 1.25 molar equivalents. In someembodiments, in an amount in the range of from about 1.0 to about 1.1molar equivalents. In other embodiments, in an amount of about 1.01molar equivalents. This reaction takes place in the presence of asuitably selected oxidizing agent or oxidizing agent system, such asNa₂SO₃/air, Na₂S₂O₅/air, NaHSO₃/air, DDQ, OXONE® or TEMPO® incombination with sodium hypochlorite. In some embodiments, Na₂SO₃/air orNa₂S₂O₅/air is used. The oxidizing agent or oxidizing agent system ispresent in an amount in the range of from about 0.90 to about 1.5 molarequivalents. In some embodiments, in an amount in the range of fromabout 0.95 to about 1.3 molar equivalents. In other embodiments, in anamount of about 1.3 molar equivalents, and still in other embodiments,in an amount of about 1.0 molar equivalents. This reaction takes placein water or in an organic solvent such as DMF, NMP, DMA, acetonitrile orethanol. In some embodiments, the reaction medium is provided by DMF.The reaction temperature is in the range of from about 25° C. to about100° C. In other embodiments the reaction temperature is in the range offrom about 55 to about 65° C.

One of ordinary skill in the art will recognize that when compound offormula (VI-S) is reacted with a salt form of compound of formula(VII-B) in an organic solvent, then the reaction is run in the presenceof a suitably selected organic or inorganic base such as such as NMM,TEA and K₂CO₃. In some embodiments, K₂CO₃ is used as such base. One ofordinary skill in the art will further recognize that the base ispresent to neutralize the salt form of compound of formula (VII-B) andthereby liberate the diamine compound of formula (VII-B). One ofordinary skill in the art will further recognize that compound offormula (VI-B) may alternatively be reacted with compound of formula(VII-B) as its corresponding salt form in water, in the presence of asuitably selected acid such as HCl, H₂SO₄, and other acids that behavelike hydrochloric and sulfuric acids in these conditions.

Powder X-ray diffraction patterns listed herein were measured using anXPERT-PRO diffractometer system. The sample was backloaded into aconventional x-ray holder and tested at 25° C. The sample was scannedfrom 4.01®2θ to 40.98®2θ with a step size of 0.017002θ and a time perstep of 17.44 seconds. Instrument voltage and current settings were 45kV and 40 mA.

The present invention is further directed to a crystalline hemi-tartrateof compound of formula (I-A). The crystalline hemi-tartrate of compoundof formula (I-A) may be characterized, for example, by its powder XRDpattern, an example of which is shown in FIG. 1 herein.

In an embodiment, the crystalline hemi-tartrate of compound of formula(I-A) may be characterized by its powder X-ray diffraction patterncomprising the peaks as listed in Table 1, below.

TABLE 1 XRD Peaks Pos. [°2θ] FWHM [°2θ] d-spacing [Å] Rel. Int. [%] 6.490.15 13.62 100 8.58 0.17 10.30 48 9.17 0.20 9.64 5 10.35 0.13 8.55 1010.75 0.20 8.23 23 12.92 0.20 6.85 4 15.37 0.40 5.77 1 16.72 0.40 5.30 617.46 0.20 5.08 6 18.89 0.17 4.70 9 20.72 0.54 4.29 2 22.14 0.40 4.02 423.60 0.22 3.77 24 25.92 0.80 3.44 2 28.09 0.54 3.18 1 29.88 0.27 2.99 135.53 0.80 2.53 0.2

In an embodiment of the present invention, the crystalline hemi-tartrateof compound of formula (I-A) is characterized by its powder XRD patternwhich comprises peaks having a relative intensity greater than or equalto about 5%, as listed in Table 2 below.

TABLE 2 XRD Peaks Pos. [°2θ] FWHM [°2θ] d-spacing [Å] Rel. Int. [%] 6.490.15 13.62 100 8.58 0.17 10.30 48 9.17 0.20 9.64 5 10.35 0.13 8.55 1010.75 0.20 8.23 23 16.72 0.40 5.30 6 17.46 0.20 5.08 6 18.89 0.17 4.70 923.60 0.22 3.77 24

In an embodiment of the present invention, the crystalline hemi-tartrateof compound of formula (I-A) is characterized by its powder XRD patternwhich comprises peaks having a relative intensity greater than or equalto about 10%, as listed in Table 3 below.

TABLE 3 XRD Peaks Pos. [°2θ] FWHM [°2θ] d-spacing [Å] Rel. Int. [%] 6.490.15 13.62 100 8.58 0.17 10.30 48 10.35 0.13 8.55 10 10.75 0.20 8.23 2323.60 0.22 3.77 24

In an embodiment of the present invention, the crystalline hemi-tartrateof compound of formula (I-A) is characterized by its powder XRD patternwhich comprises peaks having a relative intensity greater than or equalto about 20%, as listed in Table 4, below.

TABLE 4 XRD Peaks Pos. [°2θ] FWHM [°2θ] d-spacing [Å] Rel. Int. [%] 6.490.15 13.62 100 8.58 0.17 10.30 48 10.75 0.20 8.23 23 23.60 0.22 3.77 24

The present invention is further directed to a process for thepreparation of a hemi-tartrate of compound of formula (I-A). Thehemi-tartrate of compound of formula (I-A) may be prepared according tothe following process.

Compound of formula (I-A) is dissolved in an organic solvent such asdenatured ethanol, methanol or IPA. In some embodiments, denaturedethanol is used. In other embodiments, a mixture of denatured ethanoland isopropanol is used.

Water is optionally removed from the compound of formula (I-A) solution.In some embodiments, water is removed azeotropically. For example, byadding a suitably selected organic solvent, such as cyclohexane, to thecompound of formula (I-A) solution, and subjecting the resulting mixtureto azeotropic distillation.

With or without water removal from it, the solution of compound offormula (I-A), is heated to a temperature in the range of from about 35°C. to about reflux, for example to a temperature of about 50° C., andL-tartaric acid is added to the heated mixture. L-tartaric acid is addedin an amount in the range of from about 0.25 to about 1.0 molarequivalents. In some embodiments, in an amount of about 0.5 molarequivalents.

The mixture with the added L-tartaric acid is heated to a temperature inthe range of from about 50° C. to about reflux. In some embodiments, toa temperature of about 50° C. In other embodiments, to a temperaturefrom about 70° C. to about 75° C. The resulting mixture is optionallyfiltered. With or without filtration, a tartrate solution is obtained.

Embodiments of this invention optionally include one or two of thefollowing additional steps to obtain solid compound-of-formula-(I-A)hemi-tartrate.

Cooling the tartrate solution. In some embodiments, this cooling iseffectuated to a temperature below room temperature. In otherembodiments, the cooling is effectuated to a temperature of from about0° C. to about −5° C. A precipitate of the hemi-tartrate of compound offormula (I-A) is obtained. In addition, this precipitate can be furtherisolated. Such isolation is achieved by washing the precipitate withcold organic solvent, and further optionally drying the precipitateaccording to known methods, for example under vacuum and/or underelevated temperature.

The present invention is further directed to a process for therecrystallization of the hemi-tartrate of compound of formula (I-A). Insome embodiments, the recrystallization is done as follows.

Dissolving hemi-tartrate of compound of formula (I-A) in a mixture ofwater and an organic solvent, such as denatured ethanol, and optionallyfiltering the resultant mixture. Illustrative examples of suchwater/organic solvent mixture are given by an about 1% (vol/vol)water:denatured ethanol mixture; a mixture of water and denaturedethanol, wherein the water is present in from about 1.0% to about 1.5%by weight; and a mixture of water and denatured ethanol, wherein thewater is present in about 1.4% by weight. Removing water from theso-prepared mixture to yield a mixture with boiling point of betweenabout 70° C. and about 80° C. In some embodiments, such boiling point isbetween about 70° C. and about 75° C. In other embodiments, such boilingpoint is between about 78° C. and about 80° C. This water removal isaccomplished in some embodiments by azeotropic distillation. Theresulting mixture is subsequently optionally filtered.

Embodiments of this invention optionally include one or two of thefollowing additional steps to obtain recrystallizedcompound-of-formula-(I-A) hemi-tartrate. Cooling the mixture to yield aprecipitate of the crystalline hemi-tartrate of compound of formula(I-A). For example, cooling to a temperature of about 0° C. Subsequentlyisolating of the precipitate. For example by filtration, which isoptionally washed with cold organic solvent. The washed precipitate isoptionally dried according to known methods, for example under vacuumand/or under elevated temperature.

In another aspect, the present invention is directed to a process forthe recrystallization of the hemi-tartrate of compound of formula (I-A)as follows.

Dissolving hemi-tartrate of compound of formula (I-A) in a mixture oforganic solvents, such as a mixture of methanol and denatured ethanol.Optionally heating such mixture to a temperature greater than about roomtemperature. Examples of such temperature include about refluxtemperature, and a temperature in the range of from about 50° C. toabout 60° C. Subsequently, optionally filtering the resultant mixture.

The so-prepared mixture is subsequently cooled to yield a precipitate ofthe crystalline hemi-tartrate of compound of formula (I-A). In someembodiments, it is cooled to about 0° C. In some embodiments, suchcooling is effectuated in a step-wise manner. The so-formed precipitateis subsequently isolated. In some embodiments, the isolation iseffectuated by filtration, and the isolated precipitate is optionallywashed with cold organic solvent. The precipitate is optionally driedaccording to known methods, for example under vacuum and/or underelevated temperature.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum or a syrup.

Example 1, STEPS A-D describe recipes/procedures for the synthesis ofthe title compounds. Several batches of said compounds were preparedaccording to the recipes/procedures as described below. The physicalproperties (e.g., MS⁺, ¹H NMR, etc.) listed at the end of the synthesisdescriptions below are a listing of the physical properties measured fora representative sample of the prepared compound.

Example 1[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

Step A

A 100 L glass-lined reactor was charged with2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propylamino]-benzonitrile (5.41kg, 19.8 mol) and toluene (47.13 kg). The resultant suspension wasstirred and cooled to about 0 to −5° C. Next, 1.0M diisobutylaluminumhydride (DIBAL-H) in toluene (40.55 kg, 47.33 mol) was added, vianitrogen pressure, while maintaining the internal reaction temperatureat <2° C. After completing the addition, the resultant reaction solutionwas warmed to about 5-10° C. and the reaction monitored for completionby HPLC. Cold ethyl acetate (4.89 kg) was then added over 30 min and theresultant mixture stirred for 15-20 minutes. The resultant mixture(containing2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propylamino]-benzaldehyde) wastransferred to a 100 L glass receiver and rinsed with toluene (1.00 kg).

Step B

A cold solution of water/sulfuric acid (27.05 kg/2.26 kg) to each, a 100L Hastelloy reactor and a 100 L glass lined reactor. The resultantaqueous acid solutions were stirred and cooled to about 2-5° C.Maintaining the temperature <30° C. at all times, 50% (by volume) of themixture prepared in STEP A above was added to each aqueous sulfuric acidsolution. The resultant suspension was checked for pH (target pH of 4-5)and stirred at about 20-25° C. for about 1.5-2 h. The suspensions werethen cooled to about 10-15° C. and the pH of the suspensions adjusted topH˜11-12, by adding 6N sodium hydroxide (16.12 kg, 81.42 mol), over 20min. The resultant mixtures were then stirred to an additional 15-20minutes, the agitation was then stopped and the phases allowed toseparate.

The organic phases were removed from the top of each reactor via vacuumand combined. Then the aqueous phase and middle oil phases were drainedvia the bottom valve of each reactor and discarded. The combined organicphase was concentrated at ˜40° C. to yield a solid. This solid wastransferred to drying trays and dried (60 Torr, 30-35° C.) overnight toyield solid2-Methyl-4-[3-(1-methyl-piperidin-4-yl)-propylamino]-benzaldehyde.

Step C

In a 100 L glass-lined reactor, sodium metabisulfite (Na₂S₂O₅) (1.96 kg,9.79 mol) was dissolved in purified water (54.63 kg), followed by theaddition of 3,5-dimethyl-1,2-benzenediamine-2HCl (2.07 kg, 9.86 mol) andthe resultant mixture stirred at about 20-25° C. to effect solution.Next, concentrated hydrochloric acid (1.65 kg, 16.79 mol) was added,followed by addition of2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propylamino]-benzaldehyde,prepared as in STEP B above (2.74 kg, 9.79 mol) and the resultantmixture stirred at about 23-27° C. to effect solution. The resultantmixture was heated to about 57-62° C. and monitored for completion byHPLC.

The reaction mixture was cooled to about 20-25° C. and then half of thevolume (˜30 L) was then added, via a metering pump, to a stirring 50 Lglass reactor system containing a solution of potassium carbonate (3.9kg, 28.2 mol) dissolved in purified water (15 kg), resulting in theformation of a precipitate. The precipitated product was stirred for ˜1h and then allowed to settle. The clear supernatant (˜20 L) was removedfrom the top of the 50 L reactor system and purified water (˜20 kg) wasadded. The resultant mixture was stirred for 10 min, filtered, washedwith water (13 kg) and dried at 35-40° C. under vacuum to yield solid[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine.

MS: [M=H]⁺=393

¹H NMR (600 MHz, Methanol-d₆) δ pp, 1.38-1.43 (m, 2H), 1.43-1.52 (m,2H), 1.53-1.61 (br, 1H), 1.64-1.71 (m, 2H), 1.90-1.96 (br, m, 2H), 2.42(s, 3H), 2.53 (s, 3H), 2.54 (s, 3H), 2.74 (s, 3H), 2.78-2.86 (br, m,2H), 3.15-3.36 (m, 2H), 3.36-3.47 (m, 2H) 4.35 (s, 1H), 6.90 (s, 1H),7.20 (s, 1H), 8.44 (br, s, 1H)

Step D: Preparation of Hemi-Tartrate of[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

In a 100 L Hastelloy reactor,[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine,prepared as in STEP C above (6.58 kg, 15.56 mol) was dissolved indenatured ethanol (31.00 kg, 95/5 ethanol/2-propanol) at about 48-52° C.After stirring for 15 minutes, the resultant hazy solution was cooled toabout 25-30° C. Magnesium sulfate (0.60 kg) was added and the resultantmixture was stirred an additional 30 minutes. The magnesium sulfate wasfiltered over CELITE® (0.30 kg) and the resultant clear solution(KF=0.22%) was transferred to a clean glass lined 100 L glass-linedreactor and heated to about 48-52° C. A solution of L-tartaric acid(1.16 kg, 7.73 mol) in denatured ethanol (10.0 kg) was charged to thereactor over 20 minutes. The resultant mixture was heated to about70-75° C. and then aged for 1 h. The resultant yellow slurry was cooledto about 0-5° C. over a 2 h period and then aged for 20 min. The product(as a precipitate) was filtered, washed with cold denatured ethanol(5.20 kg), then dried at about 75-80° C. under vacuum to yield the[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine,as its corresponding hemi-tartrate solid salt.

Step E: Recrystallization

In a 100 L Hastelloy reactor, the hemi-tartrate of[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine,prepared as in STEP D above (5.19 kg, 11.10 mol) was dissolved in amixture of denatured ethanol (32.40 kg, 95/5 ethanol/2-propanol) andwater (2.62 kg) at about 75-78° C. The resultant solution was cooled toabout 50-55° C. and polish filtered (to remove any foreign particles)into a clean 100 L glass-lined reactor, followed by a rinse withdenatured ethanol (4.15 kg). Denatured ethanol (25.62 kg) was added andthe resultant solution was stirred and heated to about 78-80° C. toatmospherically distill off 51 L of the solvent. The resultant solutionwas cooled to about 55-60° C. and additional denatured ethanol (27.63kg) was added, followed by heating to about 78-80° C. to atmosphericallydistill off 27 L of the solvent. The resultant solution was then cooledto about 50-55° C., seeded (2.0 g, 4.3 mmol), then further cooled toabout 18-22° C. and then stirred for 1 h. The resultant precipitate wasfiltered, washed with denatured ethanol (5.00 kg) and dried at about75-80° C. under vacuum to yield the solid hemi-tartrate of[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine.

m.p. 179° C.

The ¹H NMR of a sample of the hemi-tartrate of[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-aminewas as follows:

¹H NMR (300 MHz, Methanol-d₄) δ ppm 1.34-1.75 (m, o, 7H), 1.88-1.99 (br,m, 2H), 2.42 (s, 3H), 2.53 (s, 3H), 2.54 (s, 3H), 2.75 (s, 3H),2.76-2.89 (o, m, 2H), 3.35-3.48 (m, 4H), 4.35 (s, 1H), 6.90 (s, 1H),7.20 (s, 1H), 8.44 (br, s, 1H)

Example 2[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

To a 4 mL vial were added 3,5-dimethyl-benzene-1,2-diamine.2HCl (69 mg,0.33 mmol),4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde(92 mg, 0.33 mmol), 2,3-dichloro-5,6-dicyano-p-benzoquinone (75 mg, 0.33mmol), and DMF (2 mL). After addition of triethylamine (0.09 mL, 0.66mmol), the resultant mixture was stirred for 5 hours at roomtemperature. The resultant mixture was then diluted with 1N NaOH (7.5mL) and dichloromethane (7.5 mL). The organic layer was concentrated andpurified by flash chromatography to yield the title compound.

MS: [M=H]⁺=393

¹H NMR (600 MHz, Methanol-d₆) 6 pp, 1.38-1.43 (m, 2H), 1.43-1.52 (m,2H), 1.53-1.61 (br, 1H), 1.64-1.71 (m, 2H), 1.90-1.96 (br, m, 2H), 2.42(s, 3H), 2.53 (s, 3H), 2.54 (s, 3H), 2.74 (s, 3H), 2.78-2.86 (br, m,2H), 3.15-3.36 (m, 2H), 3.36-3.47 (m, 2H) 4.35 (s, 1H), 6.90 (s, 1H),7.20 (s, 1H), 8.44 (br, s, 1H)

Example 34-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde

To a 5-L jacketed reactor equipped with overhead mechanical stirrer,nitrogen inlet, thermocouple probe, and J-Kem syringe pump was added4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbonitrile(160.0 g, 585 mmol) in THF (1.6 L). The resultant mixture was cooled to5° C., and diisobutylaluminum hydride (DIBAL-H) (1 M in toluene, 1.755L, 1.755 mol) was added by syringe pump over 2.33 hours, whilemaintaining an internal reaction temperature of <8° C. After completionof the addition, the resultant mixture was warmed to 20° C. over 40 min,then maintained an additional 3 hours at room temperature. The reactionwas then quenched with aqueous H₂SO₄ (110 mL of sulfuric acid in water,2 L total volume). The quench was executed over 1 hour with a jackettemperature of 0° C. and an internal temperature of 20-30° C. and wasobserved to be highly exothermic. (A Rochelle's salt quench was alsoexplored. This approach was successful, but required long stirring times(after the quench) to yield two clear layers. An HCl quench was alsoemployed and produced results similar to the sulfuric acid quench.) Theresultant mixture was then stirred for 45 minutes and the aqueous layerand suspended solids were drained. The pH of the aqueous layer wasadjusted to pH˜10.6 with 50% NaOH (336 mL). Extraction of the aqueouslayer (2×2 L dichloromethane) and concentration of the combined aqueouslayers yielded an oil, which was used in the next step without furtherpurification.

MS (electrospray): exact mass calculated for C₁₅H₂₃N₅, 276.20; m/zfound, 277.1 [M+H]⁺.

Example 4[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

To a 2 L Erlenmeyer flask were added 3,5-dimethyl-benzene-1,2-diamine.2HCl (54.85 g, 262.3 mmol) and Na₂S₂O₅ (64.82 g, 341.0 mmol), as wellas4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde(prepared as in Example 3 above) (72.5 g, 262.3 mmol) in DMF (725 mL).After addition of triethylamine (73.1 mL, 524.6 mmol), the resultantmixture was warmed on a hot plate with stirring to 90° C. and held atthis temperature for 2 hours. The resultant mixture was thenconcentrated to near dryness and partitioned between dichloromethane(0.7 L) and 1 N NaOH (1 L). The resultant mixture was stirred for 1 hourand then filtered to isolate the voluminous solid which had formed. Thesolids were dried and then partitioned between chloroform (700 mL) andsaturated aqueous NaHCO₃ (700 mL). The layers were separated, theorganic layer was dried over sodium sulfate and concentrated to aresidue. The residue was recrystallized in hot heptane/ethyl acetate(1.8:1, 840 mL total volume) with initial hot filtration (˜1 g of oilyresidues removed) and final filter cake washing with heptane/ethylacetate (3:1, 250 mL total volume) to yield the title compound as acrystalline solid.

¹H-NMR: (400 MHz, CD₃OD) δ, 8.43 (s, 1H), 7.20 (s, 1H), 6.89 (s, 1H),3.42 (t, J=7.0, 2H), 2.89-2.82 (m, 2H), 2.54 (s, 3H), 2.53 (s, 3H), 2.42(s, 3H), 2.24 (s, 3H), 2.03-1.94 (m, 2H), 1.77-1.70 (m, 2H), 1.69-1.61(m, 2H), 1.38-1.18 (m, 5H).

MS (electrospray): exact mass calculated for C₂₃H₃₂N₆, 392.27; m/zfound, 393.2 [M+H]⁺.

Elemental Analysis for C₂₃H₃₂N₆.0.25H₂O: Calculated: C, 69.58; H, 8.25;N, 21.17; Measured: C, 69.45; H, 8.06; N, 21.30.

Example 5 Hemi-tartrate of[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

To a 50-mL reactor equipped with an overhead mechanical stirrer, liquidaddition funnel, reflux condenser, internal temperature probe anddynamic nitrogen inlet were added[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine(1.01 g, 2.58 mmol) and EtOH (15 mL, 200 proof). The resultantheterogeneous solution was heated to 50° C., at which point the mixturewas observed to become a homogeneous solution. At 50° C., a solution ofL-tartaric acid (0.193 g, 1.29 mmol) dissolved in EtOH (5.0 mL, 200proof) was added dropwise over 2.0 minutes. A slight precipitate wasobserved at the site of addition; however, the precipitate was notpersistent. After completion of the addition, the resultant homogeneoussolution was aged at 50° C. for 30 minutes. The resultant solution wasthen cooled to about 20° C. at which time nucleation was observed afterageing for ˜30 min. The resultant slurry was aged at about 20° C. for4.5 hours. The solids were collected by suction filtration and dried ina vacuum oven (under house vacuum) at 50° C. for 2.5 days. Aftercomplete solvent removal, the title compound was obtained as acrystalline solid.

Example 6 Recrystallization of Hemi-tartrate of[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

A representative sample of the hemi-tartrate of compound of formula(I-A), prepared as described in Example 5 above, was recrystallized asfollows.

To a 500-mL, round bottom flask equipped with an overhead mechanicalstirrer, reflux condenser and internal temperature probe were added thehemi-tartrate of[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine(8.03 g, 17.2 mmol) and EtOH (160 mL, 200 proof). The resultantheterogeneous mixture was warmed to reflux (77.3° C.). At reflux, H₂Owas added dropwise via syringe (1.6 mL) and a homogeneous solution wasachieved. The resultant solution was aged at reflux for 30 minutes thencooled to about 21.3° C. over a 90-minute period. Once this temperaturewas reached, nucleation was observed after ˜30 min. The resultant slurrywas aged at this temperature for an additional 4 hours. The solids werecollected by suction filtration and dried at room temperature underhouse vacuum for 20 hours. The cake was further dried at 50° C. in avacuum oven for 20 hours to yield the title compound as a crystallinesolid.

Example 8[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

To a 2 L Erlenmeyer flask were added4-fluoro-3-methyl-benzene-1,2-diamine.HCl (46.32 g, 262.3 mmol), Na₂S₂O₅(64.82 g, 341.0 mmol), and4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde(72.5 g, 262.3 mmol) in DMF (725 mL). To the resultant mixture was thenadded triethylamine (36.6 mL, 262.3 mmol), and the reaction was warmedon a hot plate with stirring to 90° C. and held at this temperature for2 hours. The resultant mixture was then concentrated to near dryness andpartitioned between dichloromethane (1 L) and 1 N NaOH (1 L). Afterseparation of the layers, the aqueous layer was extracted a second timewith dichloromethane (1 L). The combined organic layers were then washedwith saturated aqueous NaHCO₃ (1.6 L). The organics were then extractedwith a 1 M mono/dibasic phosphate buffer (pH 5.62, 1.23 L). The aqueouslayer was then basified with 50% NaOH (80 mL) to pH 10.8. The resultantheterogeneous layer was then extracted with dichloromethane (1.5 L and500 mL), and the combined organics were concentrated to yield the titlecompound.

The title compound was recrystallized from hot heptane/ethyl acetate(2:1, 1.15 L total volume) with initial hot filtration and final filtercake washing with heptane/ethyl acetate (3:1, 250 mL total volume) toyield the title compound as a crystalline solid.

¹H-NMR: (400 MHz, CD₃OD) 6, 8.45 (s, 1H), 7.37 (dd, J=8.8, 4.4 Hz, 1H),6.99 (dd, J=10.3, 8.8 1H), 3.42 (t, J=7.0, 2H), 2.89-2.82 (m, 2H), 2.54(s, 3H), 2.49 (d, J=1.6 Hz, 3H), 2.24 (s, 3H), 2.03-1.94 (m, 2H),1.77-1.70 (m, 2H), 1.69-1.61 (m, 2H), 1.38-1.18 (m, 5H).

MS (electrospray): exact mass calculated for C₂₂H₂₉FN₆, 396.2; m/zfound, 397.2 [M+H]⁺

Elemental Analysis for C₂₂H₂₉FN₆: Calculated: C, 66.64; H, 7.37; N,21.19. Measured: C, 66.31; H, 7.61; N, 21.19.

Example 9[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

Step A

4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbonitrile(10.0 g, 36.6 mmol) was slurried in dry toluene (80.7 g) under anitrogen atmosphere. At 3-10° C., diisobutylaluminum hydride (DIBAL-H)(20% in toluene) (62.6 g, 88.0 mmol) was added over 80 min. Theresulting mixture was kept at 10-20° C. for 65 min, then ethyl acetate(9.0 g, 102.1 mmol) was added over 15 min. After stirring for 30 min atroom temperature, the resulting yellow solution was added dropwise to asolution of 37% aqueous hydrochloric acid (16.0 g, 162.4 mmol) in water(70.0 g) over 60 min at about 20° C. (exothermic reaction, gasformation). The resulting biphasic mixture was stirred at roomtemperature over night, then sodium hydroxide (30% in water) (34.1 g,255.8 mmol) was added over 20 min, resulting in the formation of a thirdlayer (orange oil). The mixture was stirred at 35-40° C. for 30 min,then the layers were allowed to separate and the aqueous layer and theorange middle layer were removed. The toluene layer was then extractedwith a mixture of 37% aqueous hydrochloric acid (3.60 g, 36.5 mmol) andwater (60.4 g) at room temperature. The aqueous layer (containing4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde)was used in the next step without further purification or productisolation.

Step B

In a clean reactor, sodium metabisulfite (4.87 g, 25.6 mmol) and3,5-dimethyl-benzene-1,2-diamine .1.5HCl (4.87 g, 25.6 mmol) wereslurried in water (64.9 g). 37% Aqueous hydrochloric acid (3.61 g, 36.5mmol) was added. To the resulting mixture was then added the aqueouslayer solution prepare din STEP A above, over 9 min at room temperature(slightly exothermic). The resulting mixture was then heated to 55-65°C. and maintained at this temperature for 2-3 hours (open reactor, O₂from air). Upon completion of the reaction (as determined by HPLC), theresulting mixture was cooled to room temperature and filtered to removeany insoluble salts that had precipitated.

Step C

Potassium carbonate (25.3 g, 183.0 mmol) was dissolved in water (100.0g) at room temperature, 2-methyltetrahydrofurane (9.0 g) was added, andthen the filtrate as prepared in STEP B was added dropwise over 60 min,resulting in precipitation of the desired product. The resultingsuspension was stirred overnight at room temperature, the precipitatewas isolated by filtration and washed with water (60.5 g), to yield thetitle compound as a yellow solid.

Example 10[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

Step A

4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde(prepared from4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbonitrileby reduction with Raney-Nickel) (20.0 g, 72.4 mmol) was suspended inwater (60.0 g) at room temperature. Hydrochloric acid (37% in water) wasadded dropwise until the solid had completely dissolved (10.0 g, 101.5mmol).

Step B

A 1 L-reactor was then charged with sodium sulfite (9.15 g, 72.6 mmol)and 3,5-dimethyl-benzene-1,2-diamine .2HCl (15.2 g, 72.7 mmol). Thesolids were slurried in water (120.0 g) at room temperature andhydrochloric acid (37% in water, 4.25 g, 43.1 mmol) was added, followedby the addition of water (20.0 g). The resulting mixture was stirred forapprox. 5 min, then heated to 45-50° C. The solution prepared in STEP Awas added in 2 portions over 40 min, and the resulting mixture stirred(open reactor, O₂ from air) for 2 h 20 min at 55-62° C. The resultingmixture was then cooled to 45° C. and sodium hydroxide (30% in water)(11.5 g, 86.3 mmol) followed by 2-methyltetrahydrofurane (200.0 g) wereadded. After the pH was adjusted with sodium hydroxide (30% in water)(27.3 g, 204.8 mmol), the resulting biphasic mixture was stirred at45-52° C. for 25 min. The resulting phases were separated and theaqueous layer was removed. To the organic layer was added water (100.0g) and the resulting mixture stirred at 45-52° C. for 20 min. Theresulting phases were again allowed to separate and the aqueous layerwas removed. To the organic layer was added dropwise, cyclohexane (122.0g) over approx. 60 min at 50° C. After the addition was complete, theresulting mixture was slowly cooled to room temperature, during whichtime crystallization set in spontaneously. The resulting mixture wasmaintained at 0° C. for 2 h, the solid was isolated by filtration,washed with cyclohexane (61.0 g) and dried in vacuo at 65° C. to yieldthe title compound as a light yellow solid.

Example 11[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

Step A

4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde(prepared from4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbonitrileby reduction with Raney-Nickel) (22.5 g, 81.4 mmol) was suspended inwater (67.7 g) at room temperature. Hydrochloric acid (37% in water)(9.67 g, 98.1 mmol) was added dropwise until the solid had completelydissolved.

Step B

A 500 mL-reactor was charged with sodium sulfite (10.30 g, 81.8 mmol)and 3,5-dimethyl-benzene-1,2-diamine .2HCl (17.10 g, 81.7 mmol). Thesolids were slurried in water (135.6 g) at room temperature andhydrochloric acid (37% in water) (6.40 g, 64.9 mmol) in water (21.6 g)was added. The mixture resulting was heated to 45-50° C. in 20 min. Tothe resulting mixture was then added dropwise, over 30 mins the solutionprepared in STEP A. The resulting mixture was then heated to 60° C. for2.5 h (open reactor, O₂ from air). Upon completion of the reaction (asmonitoring by HPLC), the resulting mixture was filtered to remove anyinsoluble salts that had precipitated.

Step C

In a clean 500 mL-reactor, potassium carbonate (56.27 g, 407.2 mmol) wasdissolved in water (202.5 g), and then 2-methyltetrahydrofurane (20.3 g)was added at room temperature. The filtrate prepared as in STEP B abovewas then added dropwise over 2 h. The resulting yellowish suspension wasstirred over night at room temperature, and the resulting precipitateisolated by filtration and washed with water.

The reactor was then charged with the wet product/precipitate (49.26 g)and 2-methyltetrahydrofurane (200.0 g), and the resulting mixture heatedto 50° C. to dissolve the solid. The resulting solution was washed twicewith a mixture sodium hydroxide (30% in water) (7.58 g, 60.6 mmol and7.56, 60.8 mmol, respectively) in water (40.0 g, 40.5 g, respectively)at 45-55° C. and once with water (40.1 g). After removal of the aqueouslayer, cyclohexane (135.0 g) was added dropwise over 50 min at 50° C.,during which time, crystallization was observed to set in spontaneously.The resulting mixture was then slowly cooled, then maintained at 0° C.for 1 h. The precipitate was isolated by filtration, washed withcyclohexane (60.0 g) and dried in vacuo at 65° C. to yield the titlecompound as a light yellow solid.

Example 12 Hemi-tartrate of[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

A 2 L-reactor was charged with[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine(200.0 g, 486 mmol) in a nitrogen atmosphere. Denatured ethanol (770.0g) followed by isopropanol (230 g) were added and the resulting mixturewas heated to 45° C. to yield a clear, yellow solution. To this solutionwas added a solution of L-(+) tartaric acid (36.5 g, 243 mmol) indenatured ethanol (294.0 g) at 40-50° C. over 70 min. The resultingsolution was maintained at 40-50° C. for 75 min, over which timecrystallization was observed to occur. The resulting suspension wasslowly cooled to 15° C., maintained at this temperature overnight, thencooled further to 0° C. After 3 h 15 min at 0° C., the title compound asa precipitate was isolated by filtration, washed with cold denaturedethanol (400 g) and dried in vacuo at 45° C. to yield the title compoundas a slightly yellow, crystalline solid.

Example 13 Hemi-tartrate of[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine(4.6 g, 10.8 mmol) was dissolved in denatured ethanol (24.3 g) at 40-50°C. Cyclohexane (15.6 g) was added and the resulting mixture was heatedto reflux at atmospheric pressure to distill off solvent. The azeotropicdistillation was continued until the reflux temperature reached 75° C.After distillation, denatured ethanol (12.5 g) was added and theresulting solution was stirred at 40-50° C. A solution of L-(+) tartaricacid (0.80 g, 5.4 mmol) in denatured ethanol (6.7 g) was added over 45min, and the resulting mixture maintained at 40-50° C. for 40 min, thenseeding crystals of the desired hemi-tartrate. The resulting thinsuspension was maintained at 40-50° C. for 4 h, then slowly cooled toroom temperature and maintained at room temperature overnight. Theresulting mixture was then cooled to 0° C. for 30-60 min, the resultingprecipitate isolated by filtration, washed with denatured ethanol (10.0g) in 2 portions and dried in vacuo at 40-50° C. to yield the titlecompound as a white crystalline solid.

Example 14 Recrystallization of Hemi-tartrate of[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine

A 500 mL-reactor was charged with[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-aminehemi-tartrate (24.0 g, 25.7 mmol) and methanol (63.0 g). The resultingmixture was warmed to 50° C. for 15 min, until all the solids wereobserved to dissolve. Denatured ethanol (105.0 g) was then added and theresulting solution was filtered (at 50° C.) to remove any remainingparticles. The filtrate was heated briefly to reflux, then cooled toapprox. 60° C., before seeding with crystals of the desiredhemi-tartrate. The resulting mixture was subjected to the followingtemperature profile for crystallization: 1 h at 60° C., cooling to 40°C. over 2 h, heating to 50° C. over 1 h, cooling to 30° C. over 2 h,heating to 40° C. over 1 h, cooling to 20° C. over 2 h, heating to 30°C. over 1 h, cooling to 10° C. over 2 h, heating to 20° C. over 1 h,then cooling to 0° C. over 2 h. The resulting suspension was maintainedat 0° C. for 7 h, then the resulting solid precipitate was isolated bysuction filtration, washed with denatured ethanol (3×30.0 g) and driedin vacuo at 40° C. to yield the title compound as a white crystallinesolid.

Example 154-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde

The following procedure represents a recipe for the preparation of thetitle compound. The title compound was prepared several times followingthe recipe detailed below.

A vessel at room temperature was charged with formic acid (800 mL) and4-methyl-2-(3-(1-methylpiperidin-4-yl)propylamino)pyrimidine-5-carbonitrile(100 g) and the resulting mixture stirred to yield a clear solution,then cooled to 10-15° C. Water (200 mL) was added and the resultingmixture cooled to −2 to 0° C. To the resulting mixture was then addedRANEY® nickel (160 g) maintaining the temperature at −2 to 0° C. andthen stirred at this temperature for 2-3 hours. The resulting mixturewas then filtered to remove the RANEY® nickel and the filtercake washedwith water (100 mL), The filtrate was cooled to 0-5° C. and then slowlytreated with 50% sodium carbonate solution in water (3.0 L) to adjustthe pH of the solution to pH˜10. Toluene (400 mL) was added and theresulting mixture stirred at room temperature for about 30 minutes, thenallowed to settle for about 1 hour. The resulting layers were separatedand the aqueous layer washed with toluene (400 mL×2). The combinedtoluene layer and washed were distilled at 55-60° C. to remove thetoluene, to yield the title compound as an oily residue.

To the residue was added hexane (100 mL), the resulting mixture stirredfor 30 minutes, then distilled under vacuum to yield a residue. To thisresidue was added hexane (200 mL) and the resulting mixture cooled to10-15° C., then stirred at this temperature for 1 hour, resulting in theformation of a precipitate. The resulting mixture was filtered and thefiltercake washed with hexane (50 mL) and then dried first under vacuumand then in an air oven at 30-35° C. to yield the title compound as awhite to light yellow solid.

Example 16 Oral Formulation

As a specific embodiment of an oral composition, 100 mg of the compoundprepared as in Example 1 is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size 0 hardgel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A process for the preparation of a compound of formula (I)

wherein R¹, R², R³ and R⁴ are each independently selected from the groupconsisting of H, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, phenyl, —CF₃,—OCF₃, —CN, halo, —NO₂, —OC₁₋₄alkyl, —SC₁₋₄alkyl, —S(O)C₁₋₄alkyl,—SO₂C₁₋₄alkyl, —C(O)C₁₋₄alkyl, —C(O)phenyl, —C(O)NR^(a)R^(b),—CO₂C₁₋₄alkyl, —CO₂H, —C(O)NR^(a)R^(b), and —NR^(a)R^(b); wherein R^(a)and R^(b) are each independently selected from the group consisting ofH, C₁₋₄alkyl, and C₃₋₇cycloalkyl; X¹ is C—R^(c); wherein R^(c) isselected from the group consisting of H, methyl, hydroxymethyl,dimethylaminomethyl, ethyl, propyl, isopropyl, —CF₃, cyclopropyl, andcyclobutyl; X² is N; n is 1 or 2; Z is selected from the groupconsisting of N, CH, and C(C₁₋₄alkyl); R⁶ is selected from the groupconsisting of H, C₁₋₆alkyl, and a monocyclic cycloalkyl; R⁸ is selectedfrom the group consisting of H and C₁₋₄alkyl; R⁹, R¹⁰ and R¹¹ are eachindependently selected from the group consisting of H and C₁₋₄alkyl; orpharmaceutically acceptable salt, or pharmaceutically acceptableprodrug, or pharmaceutically active metabolite thereof; comprising

reacting a compound of formula (V) with a reducing agent system; in asolvent; at a temperature in the range of from about 0° C. to about 25°C., to yield compound of formula (VI); and

reacting compound of formula (VI) with a compound of formula (VII) inthe presence of an oxidizing agent system, in a solvent, at atemperature in the range of from about 25° C. to about 100° C.
 2. Aprocess for the preparation of a compound of formula (I-A)

or pharmaceutically acceptable salt, or pharmaceutically acceptableprodrug, or pharmaceutically active metabolite thereof; comprising

reacting a compound of formula (V-S) with a reducing agent system; in asolvent; at a temperature in the range of from about 0° C. to about 25°C., to yield compound of formula (VI-S);

reacting compound of formula (VI-S) with a compound of formula (VII-A)in the presence of an oxidizing agent system, in a solvent, at atemperature in the range of from about 25° C. to about 100° C., to yieldcompound of formula (I-A).
 3. A process as in claim 2 wherein thereducing agent system is selected from the group consisting of Diabl-H,and RANEY® nickel and a source of hydrogen.
 4. A process as in claim 2,wherein the reducing agent system is DIBAL-H; wherein the DIBAL-Hispresent in an amount in the range of from about 1.0 to about 5.0 molarequivalents; and wherein the solvent in said reacting a compound offormula (V-S) is selected from the group consisting of anhydrous tolueneand anhydrous THF.
 5. A process as in claim 4, wherein DIBAL-His presentin an amount of about 2.5 molar equivalents.
 6. A process as in claim 2,wherein the reducing agent system is RANEY® nickel and a source ofhydrogen; wherein the source of hydrogen is formic acid; and wherein thesolvent in said reacting a compound of formula (V-S) is water.
 7. Aprocess as in claim 6, wherein the RANEY® nickel is present in an amountin of about 200% by weight and wherein the formic acid is present in anexcess amount.
 8. A process as in claim 2, wherein compound of formula(V-S) is reacted with the reducing agent system at a temperature ofabout 5 to about 25° C.
 9. A process as in claim 2, wherein compound offormula (VII-A) is present as its corresponding free base.
 10. A processas in claim 2, wherein the compound of formula (VII-A) is present in anamount in the range of from about 1.0 to about 1.25 molar equivalents.11. A process as in claim 10, wherein the compound of formula (VII-A) ispresent in an amount in the range of from about 1.0 to about 1.1 molarequivalents.
 12. A process as in claim 2, wherein the oxidizing agentsystem is selected from the group consisting of Na₂S₂O₅/air andNa₂SO₃/air.
 13. A process as in claim 2, wherein the oxidizing agent oroxidizing agent system is present in an amount in the range of fromabout 0.90 to about 1.5 molar equivalents.
 14. A process as in claim 13,wherein the oxidizing agent system is present in an amount of about 1.0molar equivalents.
 15. A process as in claim 2, wherein the compound offormula (VI-S) is reacted with compound of formula (VII-A) in water. 16.A process as in claim 2, wherein the compound of formula (VI-S) isreacted with compound of formula (VII-A) at a temperature in the rangeof from about 55° C. to about 65° C.
 17. A process for the preparationof a compound of formula (I-B)

or pharmaceutically acceptable salt, or pharmaceutically acceptableprodrug, or pharmaceutically active metabolite thereof; comprising

reacting a compound of formula (V-S) with a reducing agent system; in asolvent; at a temperature in the range of from about 0° C. to about 25°C.; to yield compound of formula (VI-S); and

reacting the compound of formula (VI-S) with a compound of formula(VII-B) in the presence of an oxidizing agent system, in a solvent at atemperature in the range of from about 25° C. to about 100° C., to yieldcompound of formula (I-B).
 18. A process as in claim 17, wherein thereducing agent system is selected from the group consisting of DIBAL-H,and RANEY® nickel and a source of hydrogen.
 19. A process as in claim17, wherein the reducing agent system is DIBAL-H; wherein the DIBAL-Hispresent in an amount in the range of from about 1.0 to about 5.0 molarequivalents; and wherein the solvent in said reacting a compound offormula (V-S) is selected from the group consisting of anhydrous THF andanhydrous toluene.
 20. A process as in claim 19, wherein the DIBAL-Hispresent in an amount of about 2.5 molar equivalents.
 21. A process as inclaim 17, wherein the reducing agent system is RANEY® nickel and asource of hydrogen; wherein the source of hydrogen is formic acid; andwherein the solvent in said reacting a compound of formula (V-S) iswater.
 22. A process as in claim 21, wherein the RANEY® nickel ispresent in an amount of about 20% by weight and wherein the formic acidis present in an excess amount.
 23. A process as in claim 17, whereinthe compound of formula (V-S) is reacted with the reducing agent systemat a temperature of from about 5° C. to about 25° C.
 24. A process as inclaim 17, wherein the compound of formula (VII-B) is present as itscorresponding free base.
 25. A process as in claim 17, wherein thecompound of formula (VII-B) is present in an amount in the range of fromabout 1.0 to about 1.25 molar equivalents.
 26. A process as in claim 25,wherein the compound of formula (VII-B) is present in an amount in therange of from about 1.0 to about 1.1 molar equivalents.
 27. A process asin claim 17, wherein the oxidizing agent system is selected from thegroup consisting of Na₂S₂O₅/air and Na₂SO₃/air.
 28. A process as inclaim 17, wherein the oxidizing agent system is present in an amount inthe range of from about 0.90 to about 1.5 molar equivalents.
 29. Aprocess as in claim 28, wherein the oxidizing agent system is present inan amount of about 1.0 molar equivalents.
 30. A process as in claim 17,wherein the compound of formula (VI-S) is reacted with the compound offormula (VII-B) in water.
 31. A process as in claim 17, wherein thecompound of formula (VI-S) is reacted with the compound of formula(VII-B) at a temperature in the range of from about 55° C. to about 65°C.
 32. A crystalline hemi-tartrate of compound of formula (I-A)


33. A crystalline hemi-tartrate of compound of formula (I-A)

whose powder X-ray diffraction spectrum comprises the following powderX-ray diffraction peaks: Pos. [°2θ] d-spacing [Å] 6.49 13.62 8.58 10.309.17 9.64 10.35 8.55 10.75 8.23 16.72 5.30 17.46 5.08 18.89 4.70 23.603.77


34. A process for the preparation of a hemi-tartrate of compound offormula (I-A)

comprising: dissolving the compound of formula (I-A) in an organicsolvent forming a solution; heating said solution to a first temperaturein the range of from about 35° C. to about reflux; adding L-tartaricacid to form a tartrate solution; and heating said tartrate solution toa second temperature in the range of from about 50° C. to about refluxto form a heated mixture.
 35. A process as in claim 34, wherein saidheating said first temperature is about 50° C.
 36. A process as in claim34, wherein the L-tartaric acid is added in an amount of about 0.5 molarequivalents.
 37. A process as in claim 34, wherein said secondtemperature is a temperature of about 70° C. to about 75° C.
 38. Aprocess as in claim 34, further comprising cooling said heated mixtureto a temperature in the range of from about 0° C. to about −5° C.
 39. Aprocess for the recrystallization of a hemi-tartrate of compound offormula (I-A)

comprising: dissolving the hemi-tartrate of compound of formula (I-A) ina mixture of water and an organic solvent, or in a mixture of organicsolvents; and removing a sufficient amount of water to yield a mixturewith boiling point of between about 78° C. and about 80° C.
 40. Aprocess as in claim 39, wherein the hemi-tartrate of compound of formula(I-A) is dissolved in one of the following mixtures: a mixture of waterand denatured ethanol, and a mixture of methanol and denatured ethanol.41. A process as in claim 40, wherein the hemi-tartrate of compound offormula (I-A) is dissolved in a mixture of water and denatured ethanol;and wherein the water in the mixture is present in an amount of fromabout 1% to about 1.5% by weight.
 42. A process as in claim 41, whereinsaid water is present in an amount of about 1.4% by weight.
 43. Aprocess as in claim 39, wherein said dissolving is made in a mixture ofwater and an organic solvent, and further comprising heating saidhemi-tartrate of the compound of formula (I-A) in said mixture of waterand an organic solvent to azeotropically remove the water.